NAD+-dependent pathways have been linked to the control of cellular metabolism, including some pathways involved in lipid metabolism. Prostate cancer is characterized by a lipogenic phenotype. We hypothesize that proper NAD+ metabolism is required to support the lipid-dependent nature of prostate cancer. Specifically, we posit that a trefoil of NAD+-dependent enzymes, namely Nampt, CD38 and the sirtuins control lipid metabolism to support prostate cancer cell survival, wherein the sirtuins act as the metabolic rheostat in response to changes in NAD+ levels. The goal of the proposed work is to understand how NAD+ metabolism establishes epigenetic control of lipid metabolism and prostate tumor growth. By deciphering these mechanisms, this proposal will create new insight into the process required to support tumor cell metabolism and survival. The specific aims of this proposal are 1) To determine how the Nampt-NAD+ axis regulates the epigenetic control of metabolism and survival in prostate cancer, 2) To define how the CD38-NAD+ axis controls metabolism and survival in prostate cancer, and 3) To determine the role of CD38 in the progression of prostate cancer. The results from this study will A) demonstrate how NAD+ metabolism regulates the epigenetic control of lipid metabolism; B) determine whether CD38, the main NAD'ase in cells, acts to suppress prostate cancer, and C) demonstrate how Nampt, CD38 and the sirtuins form a regulatory network to regulate prostate tumor growth. The clinical relevance of the proposal is timely. Lipid metabolism is a recognized target in many cancers, including prostate. Moreover, several small molecule Nampt inhibitors have been developed recently and are being evaluated in clinical trials. In addition, several sirtuin activators and inhibitors have been described. Therefore, it is possible that compounds with the ability to affect NAD+ metabolism and ultimately lipid metabolism will enter the clinic. Altogether, the proposed studies will define the contribution of NAD+ metabolism to prostate cancer and identify methods to reprogram tumor cell metabolism through modulation of NAD+-linked pathways. PUBLIC HEALTH RELEVANCE: Aberrant lipid metabolism is a hallmark of prostate cancer. NAD+ is involved in the control of multiple aspects of cellular metabolism. The purpose of this is to determine how NAD+ metabolism regulates survival and the lipogenic phenotype of prostate cancer so that therapeutic strategies to metabolically reprogram tumors can be developed.